title: High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial.
abstract: OBJECTIVE
  No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective.
  
  
  OBJECTIVE
  To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A.
  
  
  METHODS
  A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group.
  
  
  METHODS
  Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester).
  
  
  METHODS
  One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects.
  
  
  METHODS
  Oral AA (4 g/d) or matching placebo.
  
  
  METHODS
  Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT.
  
  
  RESULTS
  The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99).
  
  
  CONCLUSIONS
  Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00484510.
authors.affiliation: Department of Neurology, Wayne State University, Detroit, Michigan, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Michael P
authors.initials: MP
authors.lastname: McDermott
authors.forename: David N
authors.initials: DN
authors.lastname: Herrmann
authors.forename: Ahmet
authors.initials: A
authors.lastname: Hoke
authors.forename: Lora L
authors.initials: LL
authors.lastname: Clawson
authors.forename: Carly
authors.initials: C
authors.lastname: Siskind
authors.forename: Shawna M E
authors.initials: SM
authors.lastname: Feely
authors.forename: Lindsey J
authors.initials: LJ
authors.lastname: Miller
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.forename: Patricia
authors.initials: P
authors.lastname: Smith
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luebbe
authors.forename: Xingyao
authors.initials: X
authors.lastname: Wu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D018447:Medical Futility; D051379:Mice; D008875:Middle Aged; D012720:Severity of Illness Index; D013997:Time Factors; D055815:Young Adult
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid